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Bone as an active connective and endocrine tissue is influenced by hormones, physical activity, inflammatory factors, minerals, dietary components, and body weight. Bone fractures are a major cause of decreased quality of life and mortality in humans. Polycystic ovary syndrome (PCOS), is one of the most common endocrine disorders in women of reproductive age worldwide. PCOS is associated with disturbances in androgen and estrogen levels, insulin resistance (IR), obesity, as well as low-grade chronic inflammation, and gut microbiota (GM) dysbiosis, all of which may negatively or positively affect bone metabolism. However, it has not yet been well clarified whether PCOS is bone-protective or bone-destructive. This study aimed to review the association between bone health and PCOS, and summarize its related factors. PubMed, Scopus, and Web of Science databases were searched to retrieve relevant English publications investigating the relationship between bone health and PCOS. Several disorders associated with PCOS can negatively or positively affect bone metabolism. Despite some positive effects of insulin, androgens, estrogens, and obesity on bone, IR, estrogen deficiency, low-grade chronic inflammation, and GM dysbiosis may adversely affect the bone metabolism in PCOS women. Studies comparing bone mineral density or bone metabolism and the risk of bone fractures in women with PCOS have controversial results. Further studies are required to understand the mechanisms underlying bone metabolism in PCOS subjects. Moreover, prospective studies are needed to estimate the risk of bone fractures and osteoporosis in PCOS subjects.

We aimed to compare the ovarian reserve of rats exposed to oral D-galactose during prenatal and early life with rats exposed to D-galactose only during the prenatal period. Fifteen female pregnant Wistar rats were randomly divided into three groups. The first and second groups were fed a D-galactose enriched diet (35%) from the third day of pregnancy to parturition (PP) and the third day to the end of lactation (PL), respectively. The control group (C group) was fed a standard diet. The study population was the female offspring of three groups (PP', PL', and C'), in which some reproductive factors were examined between 45 and 50 days of age. When compared with the PP' group, the number of primordial follicles was significantly higher in the PL' group at PND 45-50 (40 vs. 30; p = .01); however, the antimullerian hormone level was significantly reduced in the PL' group versus control group (-2.2, 95% confidence interval [CI]: -2.83, -1.53 ng/ml p = .000), and follicle-stimulating hormone level significantly increased in PP' group versus control (4.5 mIU/ml, 95% CI: 1.40-7.62, p = .005). There was no significant difference in leukocyte infiltration or antiovarian antibody among the groups. Continued exposure to D-galactose during the lactation period inhibits the primordial follicle loss in rats in terms of producing fewer atretic follicles.

Polycystic ovary syndrome (PCOS) is a complex endocrine disorder that represents infertility in many reproductive-age women. Reduced implantation of blastocyst was proposed as an etiology for infertility in this syndrome. In this regard, many candidate genes such as leukemia inhibitory factor (LIF), LIF receptor (LIFR), glycoprotein 130 (gp130), and interleukin 11 (IL11) were proposed to be disrupted. Investigation of these genes is not ethically approved in pregnant women with PCOS. In this study, we aimed to compare the expression of LIF, LIFR, gp130, and IL11 before and during different gestational days in uterine tissues of prenatally-androgenized rat models of PCOS with control rats. The rat model of polycystic ovary syndrome was created by the injection of testosterone during prenatal life. RNA extraction and cDNA synthesis from uterine tissues were performed in both prenatal induced PCOS and control rats. Expression of LIF, LIFR, gp130, and IL11 genes was compared before pregnancy (GD0) and during pregnancy on GD0.5, GD4.5, GD5.5, and GD8.5 between two study groups (n = 6 each group) using SYBR Green real-time PCR. The expression of the LIF mRNAs significantly decreased on GD4.5, 5.5, and 8.5 in the PCOS rats compared to the controls (P-values: 0.0483, 0.0152, and 0.0043). Additionally, decreased expression of LIFR and gp130 was observed on GD0.5 to 8.5 in PCOS rats compared to controls (P-values: 0.022, 0.0480, 0.0043, 0.0022 for LIFR and 0.0189, 0.0022, 0.0087, 0.0022 for gp130). Moreover, IL-11 mRNA levels decreased in the PCOS group compared to their controls both before (P-value:0.0362) and during the gestational period (P-values:0.0085, 0.0043, 0.0389, 0.0087). Reduced expression of LIF, LIFR, gp130, and IL11 in the rats with PCOS indicates a possible disruption in the implantation and decidualization stages in this syndrome.

Background: Embryonic life is critical for the formation of ovaries in mammals, and the intrauterine environment may affect ovarian reserve. Objectives: The present study aimed to investigate the impact of prenatal D-galactose exposure on ovarian reserve in female rat offspring in their later lives. Methods: Ten pregnant Wistar rats were randomly divided into two groups. In one group, rats were fed with 35% D-galactose-enriched food from the third day to the end of pregnancy, and in the other group, rats were fed with a standard diet throughout pregnancy. Female offspring (prenatally galactose-exposed rats and non-exposed control rats) were examined in terms of hormonal levels [anti-Mullerian hormones (AMH), follicle-stimulating hormone (FSH), and estradiol (E2)] and ovarian histology at 45 - 50, 105 - 110, and 180 - 185 days of their age. Results: The number of primordial follicles significantly decreased time-dependently in prenatally galactose-exposed rats compared to controls (P-value = 0.002). In addition, decreases in AMH (3.25 vs. 7.5 ng/mL; P = 0.000) and E2 (7.9 vs. 19.5 pg/mL; P = 0.000) and increases in FSH (6.5 vs. 0.8 mIU/mL; P < 0.007) were observed in galactose-exposed rats compared to controls at 45 - 50 days of age. Conclusions: Prenatal exposure to D-galactose negatively affects ovarian reserve in female rats in their later lives. However, further investigation is needed to confirm our findings and explore underlying mechanisms.

The expression of genes involved in basic pathways, such as folliculogenesis and steroidogenesis may be affected following prenatal androgen exposure. Besides, exposure to androgens during prenatal life plays a central role in developing polycystic ovary syndrome (PCOS) in females in later life. In the present study, we aimed to examine the expression of the follicle stimulating hormone receptor (FSHR) and activin receptor (actR) genes in ovarian granulosa cells (GCs) of a prenatally-androgenized rat model of PCOS in adulthood.In the adult rat model of PCOS and their controls (n = 8 in each group), different phases of the estrous cycle were determined by vaginal smear. Total RNA was extracted from the ovarian GCs using the TRIzol protocol, a reverse transcription kit was used for complementary DNA (cDNA) synthesis, and the expression of FSHR and actR genes was measured by SYBR-Green Real-Time PCR. GraphPad Prism was used for statistical analysis of data, and the t-Student's test was used to compare the results between the two groups. PCOS rats had longer and irregular estrous cycles compared to controls. The expression of FSHR and actR genes were significantly decreased in the rat model of PCOS compared to control rats. In PCOS rats, genes expression ratios for FSHR and actR were 0.91 ± 0.11 times (P = 0.008) and 0.42 ± 0.13 times (P = 0.048) less than controls, respectively.Reduced expression of the FSHR and actR genes in ovarian GCs may be one of the mechanisms mediating PCOS-related disorders, especially abnormal ovarian folliculogenesis and ovulation dysfunction, following exposure to androgens during fetal life.

Cardiovascular diseases may originate from suboptimal intrauterine environments. We aimed to examine the effects of prenatal androgen exposure (PAE) on heart basal hemodynamic parameters and tolerance to ischemia/reperfusion (I/R) injury, in PAE adult females and males.Pregnant Wistar rats in the experimental group (n = 8) received 5 mg of testosterone (s.c. injection) on the 20th day of pregnancy, while controls received solvent. The hearts of adult female and male offspring were isolated and perfused in a Langendorff apparatus, values of left ventricular systolic pressure(LVSP), left ventricular developed pressure(LVDP), rate pressure product(RPP) and peak rates of positive and negative changes in left ventricular pressure(±dp/dt) were recorded using a power lab system.At baseline, PAE adult males demonstrated significant higher values of LVSP, LVDP, RPP and ± dp/dt, compared to controls and PAE adult females (p 0.05), while PAE adult females showed no significant differences compared to controls. In PAE adult males, LVSP, LVDP, RPP and ± dp/dt had significant decreasing trends per phases after I/R, compared to their controls and PAE females, while these decreasing trends were not statistically significant in PAE adult female rats vs. their controls.The impact of prenatal androgen exposure on adulthood cardiac function and tolerance to I/R is gender dependent, which may be partly explained by different cardiac effects of hyperandrogenism in males versus females. After prenatal androgen exposure, the baseline hemodynamic parameters of the hearts of adult males are increased; although they had less tolerance to I/R, findings however not observed in females.

Introduction: Premature ovarian insufficiency (POI) affects about 1% of women of reproductive age, with no curative treatment. Several efforts have been made to develop an animal model of POI that mimics all manifestations of this disease; however, these models are limited due to increased mortality or high toxicity. Overall, well-developed animal models may improve our knowledge of diseases and can be suitable for identifying the underlying mechanisms and detecting the optimal treatment methods. In the present study, we aimed to present a functional rat model of POI, mimicking the clinical manifestations of POI in women. Materials and Methods: This experimental study was performed in two steps. In the first step (induction of the rat POI model), a total of 40 pregnant Wistar rats were randomly divided into four groups. Three experimental groups were fed galactose-enriched diets at days 3-15 of pregnancy (group 1); on the third day of pregnancy until the end of pregnancy (group 2); and on the third day of pregnancy until the end of the weaning period (group 3). Also, group 4 (control group) was fed a standard pellet during pregnancy and breastfeeding period. In the second step of the study, the ovarian morphology (microscopic and macroscopic), reproductive hormones, and immunological and metabolic characteristics of the female offspring were examined in all experimental groups and compared with the controls at three time points, that is, postnatal days (PNDs) 45, 105, and 180 of age.Results: In this study, we presented an optimal model of POI that highly mimics the clinical manifestations of this disease in women. Conclusion: A functional rat model of POI may be suitable for increasing our understanding of this disease and filling the knowledge gaps.

Background Development of a hyper-gonadotropic hypoestrogenism condition in women Methods For this systematic review, we conducted a search of case control studies published from 1990 until August 2018 in PubMed/Medline, and Web of science, using the descriptors in the title/abstract field. A ‘pearl growing’ strategy was employed whereby, after obtaining the full text articles, reference lists of all included studies (n = 14) were reviewed for additional publications that could be used. Results We selected and categorized 14 studies according to the time of exposure to GAL into two groups of prenatal (n = 4) and postnatal (n = 10). Findings of these studies showed that the different stages of follicular development are targeted differently by galactose exposure during the prenatal and postnatal periods: The small follicles (primordial and primary follicles) are targeted by galactose toxicity during prenatal exposure and the pre-antral and antral follicles are targeted by galactose toxicity during postnatal exposure. Conclusions This systematic review shows that galactose has an ovotoxicity effect that can be used to induce appropriate POI animal models only if sufficient doses, proper onset time, and duration of prenatal exposure are taken into account. An optimized model of POI induction should manifest all the required ovarian morphological, hormonal, and estrus cycle changes.

Objectives This study aimed to examine the trends of contraception use among married reproductive age women in Tehran Lipid and Glucose study between 2002 and 2011. Methods This analysis investigated a proportion of women users and non-users of family planning, using data from 10 year population-based Tehran Lipid Glucose Study from surveys conducted in 2002, 2005, 2008, and 2011. Of the 6813, 6993, 7077, and 6789 women in the four phases mentioned, 34.1%, 33.9%, 33.5% and 35% of participants in each phase preferred to use contraception. Number of participants studied were 2506 women in 2002, 2529 women in 2005, 2594 women in 2008 and 2525 women in 2011. Results Types of methods and patterns of change in contraception differed across time. The percentage of women using traditional methods increased significantly from 25.7% in 2002 to 34.6% in 2011 (p value for trend = 0.001). Accordingly, modern contraception use showed a reverse trend. From 2002 to 2011, 61.4%, 61%, 57.7%, and 51% of married women reported currently using various modern contraceptives, respectively (p value for trend = 0.001). The proportion of users relying on condoms showed a significant increase during this decade, being 10.9% in 2002, 15.2% in 2005, 20% in 2008 and 21.9% in 2011. The prevalence of non-users for contraception was generally low; 12.7%, 8.2%, 8% and 14.3%, respectively from 2002 to 2011, but increased significantly across time (p = 0.005) Conclusion Relying on less effective contraceptive methods has increased rapidly among women in the Tehran Lipid and Glucose cohort study, a trend that could be a warning to policy makers about the possibility of higher unsafe abortion and maternal mortality/morbidity rates in the near future.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women during reproductive ages. Clinical symptoms associated with PCOS, such as hirsutism, acne, alopecia, obesity, and infertility, may lead to emotional morbidity and then impaired sexual function in those affected. During intrauterine development, the fetus may program the development of diseases during adulthood. In this study, we aimed to examine sexual function in women with PCOS, exposed to maternal androgen excess during their prenatal life compared to non-exposed PCOS patients. In this cross-sectional study, 768 married women with PCOS, aged 18-49 years, were subdivided into two groups, based on their mothers' PCOS status: women whose mothers had PCOS (N = 94) and women whose mothers did not have PCOS (N = 674). Data were collected using a questionnaire including information on demographics, anthropometric and reproductive characteristics, and the Female Sexual Function Index. Blood serum samples were collected from patients for assessment of total testosterone and sex hormone-binding globulin levels. Results revealed that sexual dysfunction was significantly higher in PCOS women whose mothers also had PCOS, compared to those whose mothers did not (38.6 vs. 25.3%, p = .01). After adjusting for confounding variables, logistic regression analysis showed that odds ratios for sexual dysfunction (total) and sexual dysfunction in the pain domain were significantly higher in the exposed PCOS women versus the non-exposed women (OR 1.81, 95% CI 1.06-3.07, p = .02 and 1.68, 95% CI 1.01-2.77, p = .04, respectively). Our study demonstrates increased sexual dysfunction in PCOS women whose mothers also had PCOS.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in reproductive-age women. Significant associations between PCOS and benign breast diseases (BBD) and a possibly potential association between PCOS and breast cancer have been reported. The etiology of these events of mammary glands in PCOS remains unclear. Animal models that show BBD and breast cancer may contribute to further understanding about these diseases. We aimed to examine the spontaneous occurrence of mammary tumors, their prevalence, and type in our rat model of PCOS. Prenatal androgen-induced PCOS rats and controls were examined in later life. Benign mammary tumors were observed in 75% and 33.33% of PCOS rats and controls during the postmenopausal period, respectively (p = .0158). Mammary tumors were non-invasive, margins of excision were normal and tumors were freely movable, in both groups. After microscopic evaluations of tumors, proliferative breast lesions and adenomas with a tubular growth pattern were observed in both groups. However, in PCOS rats, of benign tumors two had a mixed pattern of fibroadenoma/fibroma and cysts. High prevalence of benign mammary tumors was observed in our rat model of PCOS during the postmenopausal period, possibly due to hormonal imbalances during their reproductive lifespan; this model may contribute to current data available regarding the events of mammary glands in PCOS.

Context: Reproductive domains of the Tehran lipid and glucose study (TLGS) are unique in that they provide reliable information on reproduction of an urban population of West Asia. The aim of this review is to present the most important reproductive findings of TLGS. Evidence Acquisition: This review is summarizing all articles published in the context of reproductive aspects of TLGS results over the 20-year follow-up. A comprehensive databases search was conducted in PubMed (including Medline), Web of Science and Scopus for retrieving articles on the reproductive histories in context of the TLGS. Results: The mean (SD) age at menarche and menopause was 13 (1.2) and 49.6 (4.5) years respectively. While pills were the most commonly used modern methods at the initiation of TLGS, the prevalence of condoms rose sharply and significantly over the follow up duration. Among women with history of gestational diabetes, the risk of diabetes and dyslipidemia progression were 2.44 and 1.2 fold higher than others. Prevalences of PCOS and idiopathic hirsutism among reproductive age participants of TLGS were 8.5% (95% CI: 6.8% - 10.2%) and 13.0% (95% CI: 10.9% - 15.1%), respectively. Trend of cardio-metabolic risk factors among women with PCOS showed that there were no statistically significant differences between mean changes of each cardio metabolic variables between PCOS and healthy women; PCOS status also significantly associated with increased hazard of diabetes and prediabetes among women aged younger than 40 years (HR: 4.9; 95% CI: 2.5 - 9.3, P value < 0.001)) and (HR: 1.7; 95% CI: 1.1 - 2.6), P value < 0.005), respectively. Conclusions: The population based nature of TLGS provides a unique opportunity for valid assessment of reproductive issues, the results of which could provide new information for modification of existing guidelines.

Background: Environmental factors and hormonal disorders during prenatal life can impair the evolution and differentiation of fetus’s reproductive system. The aim of this study was to the examination of sperm quality and testis tissue in adult rats that had exposed to exogenous testosterone during their prenatal life. Materials & Methods: Pregnant rats divided into two experimental and control groups. In experimental group, pregnant rats daily were subcutaneously injected with 3 mg exogenous testosterone during gestational days 16-19, and controls received solvent. The reproductive system was examined in male offspring of these animals after puberty. Data analysis was performed by using the SPSS software (version 15). Distributions between groups are compared by using the Mann-Whitney test. Results: In the offspring of experimental group, motility and the number of sperm were significantly decreased (P

Thyroid hormones (THs) play a crucial role in the development of different systems during fetal life; fetal hypothyroidism (FH) is associated with reduced cardiac function and dimensions in neonates. The aim of this study is to determine whether TH deficiency during fetal life is associated with arterial structural and hemodynamic changes during adulthood. Hypothyroidism was induced by adding 0.025% 6-propyl-2-thiouracil in drinking water throughout pregnancy, while controls consumed only tap water. Hemodynamic parameters, cross-sectional area, intima-media thickness (IMT), and density of nuclei of smooth muscle cells and endothelial cells (ECs) in the aorta and mesenteric arteries were measured. Compared to controls, in the FH group, baseline systolic blood pressure (105.7 ± 3.1 vs. 87.9 ± 3.3 mm Hg, p < 0.01), diastolic blood pressure (64.4 ± 1.7 vs. 53.2 ± 2.1 mm Hg, p < 0.05), and mean arterial pressure (80.9 ± 2.1 vs. 67.1 ± 2.1 mm Hg, p < 0.01) were significantly lower. In addition, in the FH group, intensity and latency of response to phenylephrine were significantly lower and longer, respectively, as were the IMT and density of ECs in the aorta and superior mesenteric arteries. In conclusion, this study showed that TH deficiency during fetal life can have long-lasting functional and histological effects, which can compromise cardiovascular function during adulthood.

Background: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women during the reproductive age. Considering disorders reported in women with PCOS, e.g. infertility, pregnancy complications (premature delivery, caesarean section and spontaneous miscarriages), and hormonal disorders, we hypothesized that uterine contractions in PCOS rats may be different from controls. We aimed to compare uterine contractions in PCOS rats with controls. Methods: Rats in the experimental group were subcutaneously injected with 5 mg of free testosterone on gestational day 20, while controls received solvent. The contractions of isolated uterus in offspring of both groups were recorded by the power lab system, after exposure to carbachol and oxytocin. Two-way analysis of variance was used to compare results between 2 groups. Results: PCOS rats showed more irregular uterine contractions compared to controls. After exposure to carbachol, frequency, and resting tone in the PCOS rats were significantly increased compared to controls (P = 0.004, P = 0.02, respectively). After exposure to oxytocin, the frequency, resting tone and amplitude of rhythmic contractions did not differ between the 2 groups. Conclusions: Our study indicates irregular uterine contractions and different mechanical responses of isolated uterus in PCOS rats compared to controls.

Background Currently, various clinical and laboratory diagnostic methods are used to detect overt hypothyroidism during pregnancy. The Billewicz scoring index, as a clinical scale for detection of hypothyroidism, has been applied in general populations; however, its application during pregnancy remains a controversial subject of ongoing research. Objectives The purpose of this study was to evaluate the diagnostic value of Billewicz scoring index for overt hypothyroidism in a general population of Iranian pregnant women. Methods This study was conducted on 1843 pregnant women. A comprehensive questionnaire, including Billewicz scoring items, was completed, and relevant clinical examinations were performed. The participants underwent serum measurements of thyroxine (T4), thyroid hormone uptake, thyroid-stimulating hormone (TSH), and thyroid peroxidase antibody (TPOAb). Using the receiver operating characteristic (ROC) curve analysis, the optimal sensitivity and specificity were determined as values with maximum yields on the Youden and Rsquo's Index (sensitivity + specificity-1). Results The prevalence of overt hypothyroidism and subclinical hypothyroidism was 3.3% and 28.6%, respectively. Overall, 3.6%, 18.9%, and 50% of euthyroid, subclinical hypothyroid, and overt hypothyroid women were TPOAb-positive, respectively. The mean Billewicz scores of euthyroid, overt hypothyroid, and subclinical hypothyroid women were -41.16 (11.16), -17.11 (13.63), and -40.1 (11.2), respectively. Based on the Billewicz scale, at least one sign of hypothyroidism was reported in 38.84% (n, 491) of euthyroid women. Scores ≤ -26.5 (sensitivity, 100%; specificity, 90.82%) were considered as the optimal scores for predicting overt hypothyroidism (Ldquo, Norisk, and Rsquo). Conclusions The Billewicz clinical scoring system, as a reliable and inexpensive clinical tool, used along with laboratory measurements, can help screen overt hypothyroidism during pregnancy, primarily in low-resource settings.

Despite polycystic ovary syndrome (PCOS) being one of the most common endocrine disorders affecting reproductive-aged women, the etiopathogenesis and mechanisms of this syndrome remain unclear. Considering the ethical limitations in human studies, animal models that reflect many features of PCOS are crucial resources to investigate this syndrome. We aimed to introduce the most suitable rat model of PCOS that closely mimics the endocrine, ovarian and metabolic disturbances of human PCOS phenotype, while maintaining normal reproductive system morphology in adulthood, in order to further more detailed investigations about PCOS. We searched Pubmed, Science direct, and Web of science between 1990 and 2016, for relevant English manuscripts, using keywords including the "Polycystic Ovary Syndrome AND Rat Model" to generate a subset of citations relevant to our research. Included were those articles that compared at least both ovarian histology or estrous cycle and reproductive hormonal profiles in hormone-induced rat model of PCOS and controls. Differences in the findings between hormone-induced PCOS rats appear to be a result of the degree of transplacental transfer of the steroid administered into the fetus, dose and type of hormone, route of administration and timing and duration of exposure. We conclude that prenatal hormone-induced rat model with a lower dose and shorter time of exposure during the critical period of fetal development that exhibits endocrine, ovarian and metabolic disturbances similar to PCOS in women, while maintaining normal reproductive system morphology in adulthood is more suitable than postnatal hormone-induced rat model to facilitate studies regarding PCOS.

SummaryBackground and Objective Polycystic ovary syndrome (PCOS) is a common heterogeneous endocrine disorder associated with metabolic syndrome (MetS). The aim of this systematic review and meta-analysis was to provide the most reliable estimate risk of MetS in women with PCOS, compared to healthy controls. Methods A comprehensive literature search was performed in PubMed [including Medline], Web of Science and Scopus databases for retrieving articles in English language on the prevalence/incidence and odds of MetS in women with PCOS compared to healthy controls. Mantel-Haenszel methods of meta-analysis were used to present results in terms of the pooled odds ratio (OR) (95% confidence interval [CI]) using fixed/random-effects models with/without the publication bias correction, based on the various subgroups of age and study methods. Newcastle-Ottawa Scaling and The Cochrane Collaboration's risk of bias assessment tool were used to evaluate the quality of studies included. Results The search strategy yielded 2759 potentially relevant articles of which 44 articles were included for meta-analysis. Results of the meta-analysis demonstrated that the patients with PCOS regardless of age, BMI and recruitment sources of samples had higher odds of MetS compared to healthy controls (OR 2.5, 95% CI 2.0-3.2). However, adolescents with PCOS had an increased odds of MetS compared to healthy adolescent controls in population- and nonpopulation-based studies (OR 4.7, 95% CI 1.8-11.9; OR 6.1, 95% CI 6.0- 6.1, respectively). However, the odds of MetS had no differences between adults with PCOS compared to healthy controls in population-based studies. These results were confirmed by the subgroup meta-analysis of some studies using age and BMI adjustment/matching. In addition, subgroup analysis based on diagnostic criteria of PCOS showed that the OR of MetS in PCOS using NIH criteria was higher than AES and Rotterdam criteria (Pooled Overall OR based on NIH criteria = 6.05, 95% CIL: 6.0-6.04). Conclusion These findings provide some information on the real features and a broader view of this syndrome that also helps clarify conflicting results documented in the literature. Accordingly, in prevention strategies, routine screening for metabolic syndrome is suggested for adolescents with PCOS.

Impaired ovarian follicle development, the hallmark of polycystic ovarian syndrome (PCOS), is believed to be due to the changes in expression of related genes such as follistatin (FST). Expression of FST gene and methylation level of its promoter in theca cells from adult female rats, prenatally exposed to androgen excess, during different phases of the estrus cycle was determined and compared with controls. Eight pregnant Wistar rats (experimental group) were treated by subcutaneous injection of 5 mg free testosterone on day 20 of pregnancy, while controls (n = 8) received 500 ml solvent. Based on observed vaginal smear, adult female offspring of mothers were divided into three groups. Levels of serum steroidogenic sexual hormones and gonadotropins, expression and promoter methylation of the FST gene were measured using ELISA, cyber-green real-time PCR and bisulfite sequence PCR (BSP), respectively. Compared to controls, the relative expression of FST gene in the treated group decreased overall by 0.85 fold; despite significant changes in different phases, but no significant differences in methylation of FST promoter. Our results reveal that manifestation of PCOS-like phenotype following prenatal exposure to excess androgen is associated with irregularity in expression of the FST gene during the estrus cycle.

New Findings What is the central question of this study? Would it be possible to produce a rat model of polycystic ovary syndrome (PCOS), in which the fetuses are exposed to testosterone for a short time and exhibit both endocrine and ovarian disturbances similar to PCOS, while maintaining normal reproductive system morphology in adulthood? What is the main finding and its importance? Prenatal exposure to a single dose of testosterone during the critical period of fetal development facilitates the production of a functional rat model of PCOS with minimal morphological disorders in adulthood. Production of a functional rat model that resembles many features of PCOS may contribute to a better understanding of this syndrome. Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women, with a prevalence of 8–12% during the reproductive years. In the present study, using prenatal exposure to a single dose of testosterone during the critical period of fetal development, we aimed to introduce an enhanced rat model that would exhibit both endocrine and ovarian disturbances similar to PCOS, while maintaining normal reproductive system morphology in adulthood. Ten pregnant rats were injected s.c. with 5 mg free testosterone on gestational day 20, while control rats received only solvent. The development and function of the reproductive system in female offspring were examined in adulthood. Prenatally androgenized offspring had irregular oestrous cycles compared with control animals, and their anogenital and anovaginal distances were increased compared with control rats (P

Background: Infertility has a varied impact on multiple dimensions of health and functioning of women. Objective: We aimed to identify the burden of infertility and its influencing factors based on a population based study conducted in four provinces of Iran. Materials and Methods: A sample of 1126 women, aged 18-45 years, was selected using the multi stage, stratified probability sampling procedure; those met the eligibility criteria were invited for further comprehensive interview. This study used the definition of infertility proposed by World Health Organization “the woman has never conceived despite cohabitation and exposure to pregnancy for a period of 1 year”. Results : The overall prevalence of lifetime infertility and current primary infertility were 21.1% (95% CI: 18.4- 23.8) and 6.4% (95% CI: 4.8-8) respectively. The probability of first pregnancy at the end of 2 years of marriage was 94% for all ever-married women. Infertility were observed as significantly higher among women age 31-35 (OR: 4.6; 95% CI: 1.9-11.5; p=0.001) and women with more than 9 years of education (OR: 2.8; 95% CI: 1.5-3.3; p

This study aimed to investigate the interactive effect of polycystic ovary syndrome (PCOS) status and obesity status on the serum levels of adipokines. In this comparative case–control cross-sectional study, 58 women with PCOS and 104 eumenorrheic non-hirsute women as the control group were recruited. They were further divided into two subgroups of overweight/obese and normal weight. The interactive effect of the PCOS status and obesity status on the circulating levels of adipokines was assessed using general linear model with the adjustment of age. A statistically significant negative interaction was reported between obesity status and PCOS status in the determination of serum adiponectin and resistin concentrations (effect size = −0.14, interaction P = 0.001, effect size = −0.15, P = 0.016). It indicated that adiponectin and resistin were significantly decreased in overweight/obese patients with PCOS compared with other subgroups. Statistically significant positive interactive effects were found between PCOS status obesity status and leptin (effect size = 0.321, interaction P = 0.036), indicating that the overweight/obese women with PCOS had the higher levels of leptin compared with the control group. Also, no interaction was reported between PCOS status and obesity status with regard to the serum levels of other adipokines. While no sufficient evidence is available with regard to the causal association between adipokines and PCOS, they may contribute to the development of PCOS and regarded as the novel biomarkers of PCOS.

It is believed that excess androgen exposure of the fetus, via altered gene expression, causes hyperandrogenism a key feature of polycystic ovary syndrome (PCOS). The aim of this study was to evaluate expression of Cytochrome P450-17 (CYP17), GATA-binding protein (GAGT6) and Steroidogenic acute regulatory protein (StAR), genes of adult female rats prenatally exposed to androgen excess, closely reflect endocrine and ovarian disturbances of PCOS in women, by comparing them during different phases of estrus cycle with those of non-treated rats. Both the adult prenatally testosterone exposed and control rats (n=23, each) were divided into four groups based on their observed vaginal smear (proestrus, estrus, metestrus and diestrus) and the relative expression of CYP17, GATA6 and StAR genes was measured in ovarian theca cells using Cyber-green Real-Time PCR. Serum sex steroid hormones and gonadotropins levels were measured using the ELISA method; a comparison of these two groups showed that there was an overall increase in the studied genes (CYP17; 2.39 fold change, 95% CI: 1.23-3.55; P

We aimed at investigating whether insulin resistance (IR)/sensitivity are impaired in obese/non-obese polycystic ovary syndrome (PCOS) and obese/non-obese healthy controls. A comprehensive literature search was performed for observational, English language studies. Meta-analysis was performed with the random effects model according to the heterogeneity. Eligible studies, involving 3037 women in four groups of: 1-obese, PCOS; 2-non-obese, PCOS, 3-obese, non-PCOS and 4-Non-obese, non-PCOS were included. Based on the insulin resistance index (HOMA-IR) analysis, the pooled mean (95% Conf. Interval) of HOMA IR in groups 1-4 were 4.38 (3.84, 4.92), 2.68 (2.16, 3.20), 2.44 (2.06, 2.82) and 1.34 (1.06, 1.63), respectively. Meta-analysis showed that group 1 (obese, PCOS patients) statistically have the highest IR and group 4 (non-obese, non-PCOS women) have the highest insulin sensitivity. Group 2 (non-obese, PCOS patients) and group 3 (obese, non-PCOS women) were between this range and they had lower IR than group 1 (obese, PCOS) and lower insulin sensitivity than group 4 (non-obese, non-PCOS). So, there were statistical differences between all groups except between groups 2 and 3. Insulin sensitivity indexes (quickie and ISI), also confirm the IR index (HOMA-IR) results. Based on different IR/sensitivity indexes, we found no evidence of any different effects of BMI ≥ 30 kg/m(2) on IR/sensitivity. In conclusion, PCOS status intensifies the adverse effects of obesity on IR, it has to be appropriately addressed in primary and secondary preventive cares and treatments provided for these women.

There is no consensus regarding the impact of polycystic ovary syndrome (PCOS) and its hormonal profile on sexual function of affected women; majority of data documented are not population based and there is a lack of studies investigating the association between hormonal profiles with sexual function in women with PCOS. We aimed to compare the sexual function of PCOS women with controls in a population-based study based on their hormonal profiles. In this cross-sectional study, sexual function (using the Female Sexual Function Index (FSFI) questionnaire) and hormonal profiles were determined in 63 PCOS subjects and 216 healthy women (controls); aged 18-45 years. A comparison of PCOS women and controls showed no statistically significant difference in total FSFI and each of its specific domain scores. There were significant positive correlations between dehydroepiandrosterone sulfate and total FSFI, orgasm and satisfaction domains in controls (r=0.156, r=0.206, r=0.275, respectively). No significant correlations between hormonal profiles and FSFI scores were found in the PCOS group, except for prolactin and orgasm (r=-0.250). In conclusion, sexual function did not differ between PCOS women and controls. High levels of androgens in women with PCOS were not associated with an improvement in sexual function.

In our previous study, we introduced a rat model of polycystic ovary syndrome (PCOS) induced by prenatal exposure to a single dose of testosterone on embryonic day 20. In the current study, we aimed to investigate whether prenatal exposure to a single dose of testosterone could also induce metabolic disturbances, especially insulin resistance in adulthood (100-110 days of age) and also to make it as an appropriate rat model of PCOS (exhibiting both reproductive and metabolic disturbances with minimum morphological disorders in reproductive system) for further studies in PCOS.Pregnant rats in the experimental group were subcutaneously injected with 5 mg free testosterone on the gestational day 20, while controls received only the solvent. Female offspring of both groups, prenatally androgenized (PNA) rats (PCOS models of rats) and controls were examined.Body weight measures showed significant increase in the PNA rats compared to controls on days 30, 45, 60 of age and in adulthood (P0.05). PNA rats showed insulin resistance compared to controls. Impaired glucose tolerance was not observed in the PNA rats compared to controls. There were no significant differences in lipid profile between the PNA and control rats (P0.05).Our study suggests that metabolic disturbances in PCOS and their severity during adult life probably depend on the particular time and levels of prenatal androgen exposure.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women, with a prevalence of 8-12% during the reproductive years. In the present study, using prenatal exposure to a single dose of testosterone during the critical period of fetal development, we aimed to introduce an enhanced rat model that would exhibit both endocrine and ovarian disturbances similar to PCOS, while maintaining normal reproductive system morphology in adulthood. Ten pregnant rats were injected s.c. with 5 mg free testosterone on gestational day 20, while control rats received only solvent. The development and function of the reproductive system in female offspring were examined in adulthood. Prenatally androgenized offspring had irregular oestrous cycles compared with control animals, and their anogenital and anovaginal distances were increased compared with control rats (P 0.001). No significant differences were observed in the lengths of the vagina and clitoris or the number of nipples between the two groups. Levels of testosterone and luteinizing hormone and the luteinizing hormone/follicle-stimulating hormone ratio were increased in prenatally androgenized offspring compared with control animals (P 0.05). The numbers of preantral and antral follicles in the ovaries of prenatally androgenized offspring were also increased compared with control rats (P = 0.07 and P 0.01, respectively). The number of corpora lutea was decreased in prenatally androgenized offspring compared with control rats. Cystic follicles were observed in the ovaries of prenatally androgenized offspring. Prenatal exposure to a single dose of testosterone during the critical period of fetal development could facilitate the development a functional rat model of PCOS in adulthood, with minimal morphological disorders in the reproductive system.

Background: Polycystic ovary syndrome (PCOS) is one of the most common reproductive disorders in women. Previous studies have shown that prenatal exposure of female fetuses to androgen can be considered an important factor in the development of PCOS. Objectives: In the present study we aimed to examine the effects of prenatal exposure of female rat fetuses to previously documented doses of testosterone on different embryonic days on the development of PCOS phenotype in adulthood. Materials and Methods: Pregnant rats were divided into four groups, experimental and control groups. Three mg of free testosterone was administered subcutaneously to experimental group 1 on gestational days 16-19, daily and 20 mg on day 20, to experimental group 2, and the controls received solvent at the same times. Female offspring of these mothers aged between 90-100 days were examined for development and function of the reproductive system. Independent-sample student t test was used to compare the results between the experimental groups and controls. Results: Anogenital distance (P < 0.001) and clitoris length were significantly increased in the offspring of both experimental groups (P < 0.001 and P < 0.05 respectively). Nipples were not formed in the offspring of experimental group 1, whereas in experimental group 2 the number of nipples was unchanged. Vaginal length was significantly decreased in the offspring of experimental group 1 (P < 0.001), whereas in experimental group 2, no significant difference was observed. In the offspring of experimental group 1, hormonal profiles did not differ, but in experimental group 2, levels of testosterone (P < 0.05) and LH (P < 0.01) were significantly increased, but estrogen (P < 0.05) and anti-Mullerian hormone levels (P < 0.001) were significantly decreased. A significant increase in the number of preantral and antral follicles was observed in the ovaries of offspring of experimental group 1 (P < 0.05); whereas there was no such a difference in experimental group 2. Conclusions: The time of prenatal exposure to androgens may have a significant role in the development of PCOS. Increased prenatal androgen levels are associated with hormonal changes and morphological disorders of the reproductive system. Therefore, avoiding exposure to androgen excess during critical periods of fetal development may prevent or reduce adulthood PCOS manifestations caused by prenatal excess androgen.

Objective The normal cut-off values for hyperandrogenaemia differ between populations. Although there are various ways to determine the normal range of hormones in a population, use of a gold standard and the 95th percentile approach are not appropriate to diagnose hyperandrogenism. This study aimed to determine normative cut-off androgen levels for Iranian women of reproductive age using k -means cluster analysis. Study design The subjects were 1126 women, aged 18–45 years, initially selected at random from women of reproductive age from different geographic regions of Iran. Serum levels of hormones were measured, and complete data were available for 923 women following the implementation of exclusion criteria. The reference group comprised 423 eumenorrhoeic non-hirsute women selected from the total population. Normative cut-off levels were computed using k -means cluster analysis ( k =3). Analyses were also conducted based on age and body mass index (BMI) groups for the 923 subjects. Results Cluster cut-off values for the total study population were similar to the 95th percentile values, whereas the percentiles for the free androgen index, total testosterone, dehydroepiandrostenedione sulphate and androstenedione were 79.3%, 74.1%, 96.7% and 71%, respectively, in the reference group. Conclusions Determination of cut-off values for hyperandrogenism based on age and BMI categories provides the most objective way of determining normal upper limits of androgen levels among Iranian women of reproductive age.